The pancreatic cancer It is the third leading cause of cancer-related death in the United States, and only 12% of patients survive five years after diagnosis. Severe pancreatic cancer is associated with metastasis, and it is this spread of secondary tumors that usually causes death, but little is known about the molecular mechanisms that drive metastasis.
In a new study, researchers at the University of California, Davis have shown that abnormal expression of the Engrailed-1 ( EN1 ) protein promotes pancreatic cancer progression and metastasis in vitro and in mouse models. The team also found that elevated levels of EN1 were associated with severe and metastatic pancreatic cancer in human patients, suggesting that EN1 may make a good target for pancreatic cancer therapies.
The results of research were published in Advanced Science.
Pancreatic cancer: a protein promotes the progression of metastases
“We have identified a new epigenetic factor that may contribute to metastasis in pancreatic cancer, which is one of the most difficult cancers to treat,” said Chang-Il Hwang, assistant professor in the UC Davis Department of Microbiology and Molecular Genetics and senior researcher. author in the newspaper. “A better understanding of these mechanisms would allow us to identify potential targets and improve patient survival.”
Metastases are an important component of pancreatic cancer progression, but researchers have not been able to identify the genetic mutations responsible for this. For this reason, Hwang thought that non-genetic factors, such as epigenetic changes or altered protein production, might be at play. His team had previously identified several transcription factors – proteins that control the production of other proteins – that are elevated in pancreatic cancers that have metastasized compared to primary tumors.
One of these proteins, EN1, is essential for the survival of neurons during development and is not usually produced in adult pancreatic cells. EN1 has been shown to promote aggressive forms of breast cancer and is also associated with poor prognosis in other tumors, including glioblastoma and adenoid cystic carcinoma of the salivary glands, but its role in pancreatic cancer has not been previously described.
The researchers tested whether inhibiting EN1 or increasing its expression affected the growth and survival of pancreatic cancer “organoids,” three-dimensional clumps of tissue grown in the lab. They found that, without EN1, pancreatic cancer cells were less likely to survive and divide, but adding extra EN1 increased the tumors' survival. Furthermore, when the researchers genetically modified mouse pancreatic cancer cell lines to produce more EN1 than usual, the cells showed increased rates of cell invasion and migration, key features of metastasis.
“It's very clear that EN1 is a really important factor behind the aggressiveness of pancreatic cancer,” said first author Jihao (Reno) Xu, a doctoral candidate in the Biochemistry, Molecular, Cellular and Developmental Biology graduate group. “When we take tumor cells and make them overexpress EN1, they become more metastatic and aggressive, and when we knock them down, they become less metastatic.”
By analyzing publicly available patient databases, the researchers also demonstrated that EN1 is important for the prognosis of human pancreatic cancer. They found that EN1 levels were elevated in a subgroup of patients with advanced pancreatic cancer, and that patients with elevated EN1 tended to have a worse prognosis.
“Patients with high levels of EN1 have shorter survival times, suggesting that it contributes to the aggressiveness of pancreatic cancer,” Hwang said.
Now, Hwang, Xu and their colleagues are working on how to translate their findings into clinical practice by testing different ways to target EN1. They also plan to continue studying other non-genetic factors that may contribute to the progression of pancreatic cancer.
“Ultimately, we want to identify new therapeutic strategies to address this disease,” Xu said.
Pancreatic cancer is known as a “silent killer” because it is usually only detected in later stages. But there is a glimmer of good news for patients: The five-year survival rate for people with the disease has risen at 13%, according to the American Cancer Society's 2024 statistics released Wednesday.
This is more than double the five-year survival rate of 6% a decade ago, noted experts at the Pancreatic Cancer Action Network ( PanCAN ).
The organization attributes the improvement to better detection and management of patients with tumors that have not spread beyond the pancreas.
“We have seen better management of people considered high risk and better survival of those with localized disease, most likely due to increased use and improvements in treatments available before surgery [neoadiuvante] and after surgery [adiuvante],” Lynn Matrisian, PanCAN's chief science officer, said in a press release from the organization.
All of this is “good news,” said Julie Fleshman, president and CEO of PanCAN, who added: “We're seeing more patients diagnosed at earlier stages and living longer.”
However, the latest data from the ACS predicts that about 66,400 Americans will receive the sad news this year that they have pancreatic cancer. Another 51,750 people are expected to die from the disease in 2024.
Both of these numbers reflect an increase in new cases and deaths.
So despite the increase in five-year survival, “not enough progress is being made for patients diagnosed with metastatic disease, and we need to continue to find better treatment options for these patients,” Fleshman said.
Pancreatic cancer also appears to be on the rise among younger women, PanCAN noted. This may be linked to increasing obesity rates and racial/ethnic demographic changes.
PanCAN's research priorities are to find an early detection strategy and accelerate treatments for pancreatic cancer patients. And we are dedicated to raising awareness of the symptoms and risk factors of pancreatic cancer,” Matrisian said.
There may be further hope on the horizon thanks to RUSH scientists who have discovered two new targets to decrease the progression of pancreatic cancer.
“Our findings highlight promising treatment avenues for one of the deadliest cancers with limited available options,” said Kalipada Pahan, Ph.D., Floyd A. Davis Professor of Neurology at RUSH and principal investigator of the study published in the journal Cancers. .
To identify effective targets for stimulating the death of pancreatic cancer cells and halting the progression of pancreatic cancer, the authors directly analyzed the serum of pancreatic cancer patients and healthy people and found two substances. Then they used monoclonal antibodies (artificial proteins that neutralize the targeted cells) to stop these two substances that promote the growth of cancer cells.
Researchers reported that monoclonal antibodies against interleukin (IL)-12 p40 homodimer and IL-12 p40 monomer could be used as novel immunotherapies for pancreatic cancer. IL-12 is a family of cytokines, substances secreted by cells of the immune system that have an effect on other cells. They play an important role in infection with four components, IL-12, IL-23, p40 homodimer, and p40 monomer.
Of the four components, only IL-12 and IL-23 were considered bioactive, and the latter two (p40 homodimer and p40 monomer) were considered nonfunctional.
“We were surprised to find a specific increase in p40 homodimer and p40 monomer in the serum of pancreatic cancer patients compared to healthy individuals,” Pahan said.
Similarly, human pancreatic cancer cells also produced higher levels of p40 homodimer and p40 monomer than normal human pancreatic cells.
“It was very refreshing to see the death of human pancreatic cancer cells, but not normal pancreatic cells, by these monoclonal antibodies,” Pahan said. “Interestingly, it appears that the two so-called inactive members of our immune system help pancreatic cancer cells to grow.”
According to this study, p40 homodimer monoclonal antibody and p40 monomer monoclonal antibody could be used as immunotherapies for pancreatic cancer.
“If these findings were replicated in cancer patients, it would open up a promising treatment avenue for this devastating group of diseases,” Pahan said.
After treatment with monoclonal antibodies, the authors also found a strong increase in the production of interferon gamma, a cytokine that plays an important role in causing and amplifying various immune responses. They also observed an increase in pancreatic tumor death and a reduction in pancreatic tumor size in the patient-derived xenograft mouse model. In this model, patients' pancreatic cancer tissues are transplanted into nude mice engineered to have deficient immune systems.
Pancreatic cancer is a highly malignant cancer commonly detected in advanced stages because it typically does not cause symptoms until it has spread to other organs. It represents approximately 3% of all cancers in the United States and has the lowest five-year relative survival rate of just 12%. Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer.
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